The present invention relates to new sulphur derivatives containing a retroamide bond, their preparation process, the new intermediates obtained, their use as medicaments, the pharmaceutical compositions containing them and the new use of such derivatives.
A subject of the present invention is the products of formula (I): 
in which:
R1 represents an phenyl or biphenyl radical optionally substituted by one or more radicals chosen from halogen atoms, the following radicals: optionally protected hydroxyl, linear or branched alkoxy containing up to 4 carbon atoms, cyano, free, salified, esterified or amidified carboxy, benzyloxy and the dioxol radical, n1 and n2, identical or different, represent the integer 0 or 1,
R2 represents a hydrogen atom or a methyl radical substituted by a phenyl, phenylthio or indolyl radical and optionally by a second phenyl radical, these phenyl, phenylthio and indolyl radicals being optionally substituted by one or more radicals chosen from halogen atoms and the following radicals: optionally protected hydroxyl, linear or branched alkoxy containing up to 4 carbon atoms, cyano, free, salified, esterified or amidified carboxy, benzyloxy, thienyl, naphthyl and phenyl, these three last radicals being themselves optionally substituted by one or more radicals chosen from halogen atoms and the following radicals: optionally protected hydroxyl, linear or branched alkoxy containing up to 4 carbon atoms, cyano and free, salified, esterified or amidified carboxy,
A represents the free, salified, esterified or amidified carboxy radical, the free or salified tetrazolyl radical, or an alkyl radical, containing up to 10 carbon atoms and substituted by a radical chosen from the following radicals: free, salified, esterified or amidified carboxy, the optionally protected hydroxyl, alkoxy containing up to 4 carbon atoms, phenoxy, phenyl, naphthyl, thienyl, indolyl and pyridyl, these radicals being optionally substituted by one or more radicals chosen from halogen atoms and the following radicals: optionally protected hydroxyl, linear or branched alkoxy containing up to 4 carbon atoms, cyano and free, salified, esterified or amidified carboxy,
1 and 2 indicating, if appropriate, the asymmetric centres of the products of formula (I), said products of formula (I) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic acids or with the mineral and organic bases of said products of formula (1).
In the products of formula (I) and in what follows:
the term linear or branched alkyl radical designates the following radicals: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl and also heptyl, octyl, nonyl and decyl as well as their linear or branched position isomers,
the term linear or branched alkoxy radical designates the following radicals: methoxy, ethoxy, propoxy, isopropoxy, linear, secondary or tertiary butoxy, pentoxy or hexoxy as well as their linear or branched position isomers,
the term halogen atom preferably designates the chlorine atom, but can also represent a fluorine, bromine or iodine atom.
The hydroxyl radical can in particular be in the form of the trifluoromethylsulphonyloxy radical.
The carboxy radical or radicals of the products of formula (I) can be salified or esterified by the various groups known to a person skilled in the art among which there can be mentioned, for example:
among the salification compounds, mineral bases such as, for example, an equivalent of sodium, of potassium, of lithium, of calcium, of magnesium or of ammonium or organic bases such as, for example, methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N,N-dimethylethanolamine, tris (hydroxymethyl) amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, N-methyl-glucamine.
The sodium or potassium salts are preferred,
among the esterification compounds, the alkyl radical in order to form alkoxy carbonyl or arylalkoxycarbonyl groups, such as, for example, methoxycarbonyl, ethoxycarbonyl, n-propoxy- and isopropoxy-carbonyl, n-butoxy-, isobutoxy- and tert-butoxy-carbonyl or benzyloxycarbonyl, these alkyl radicals can be substituted by radicals chosen for example from halogen atoms, hydroxyl, alkoxy, acyl, acyloxy, alkylthio, amino or aryl radicals such as, for example, in the chloromethyl, hydroxypropyl, methoxymethyl, propionyloxymethyl, methylthiomethyl, dimethylaminoethyl, benzyl or phenethyl groups.
There can also be mentioned the radicals formed with the remainders of easily cleavable esters such as the methoxymethyl, ethoxymethyl radicals; the acyloxyalkyl radicals such as pivaloyloxymethyl, pivaloyloxyethyl, acetoxymethyl or acetoxyethyl; the alkyloxycarbonyloxy alkyl radicals such as methoxycarbonyloxy methyl or ethyl radicals, the isopropyloxycarbonyloxy methyl or ethyl radicals.
A list of such ester radicals can be found for example in the European Patent EP 0 034 536.
By amidified carboxy is meant the groups of xe2x80x94CON(R6) (R7) type in which the identical or different R6 and R7 radicals represent a hydrogen atom or an alkyl radical having from 1 to 4 carbon atoms such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl radicals.
Among the xe2x80x94CON(R6) (R7) groups defined above, those in which the xe2x80x94N(R6) (R7) radical represents the amino, mono or dimethylamino radical are preferred.
The N(R6) (R7) radical can also represent a heterocycle which may or may not contain an additional heteroatom. There can be mentioned the pyrrolyl, imidazolyl, indolyl, piperidino, morpholino, piperazinyl radicals. The piperidino or morpholino radicals are preferred.
Examples of the protective group of the protected hydroxyl radical are given in particular in the usual book known to a person skilled in the art: Protective Groups in Organic Synthesis, Theodora W. Greene, Harvard University, printed in 1981 by Wiley-Interscience Publishers, John Wiley and Sons.
The addition salts with mineral or organic acids of the products of formula (I) can be, for example, the salts formed with the following acids: hydrochloric, hydrobromic, hydroiodic, nitric, sulphuric, phosphoric, propionic, acetic, formic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, ascorbic, alkylmonosulphonic acids such as for example methanesulphonic acid, ethanesulphonic acid, propanesulphonic acid, alkyldisulphonic acids such as for example methanedisulphonic acid, alpha, beta-ethanedisulphonic acid, arylmonosulphonic acids such as benzenesulphonic acid and aryldisulphonic acids.
More particularly there can be mentioned the salts formed with hydrochloric or methanesulphonic acids for example.
It should be remembered that the stereoisomerism can be defined in its widest sense as the isomerism of compounds having the same structural formulae, but the different groups of which are arranged differently in space.
It is understood that the definition of the products of formula (I) as defined above includes all possible stereoisomers, all racemic modifications, all optical isomers and all mixtures of these products which would have the activity indicated hereafter.
The products of formula (I) contain in particular two centres {circle around (1)} and {circle around (2)}, {circle around (1)} being asymmetrical and {circle around (2)} being asymmetrical when R2 does not represent a hydrogen atom. A particular subject of the present invention is the products of formula (I) in which the first asymmetrical centre {circle around (1)} is preferably in R form, the second centre {circle around (2)} can preferably be in racemic or enantiomeric R or S form.
A particular subject of the present invention is the products of formula (I) as defined above, in which R1, R2, and n2 have the meanings indicated above, n1 represents the integer 1, and A represent the free, salified, esterified ou amidified carboxy radical or an alkyl radical, containing at most 10 carbon atoms and substituted by a radical chosen from the free, salified, esterified ou amidified carboxy radicals, optionally protected hydroxyl radicals, alkoxy radicals containing at most 4 carbon atoms, and the phenoxy radical, said products of formula (I) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic acids or with mineral and organic bases of said products of formula (I).
A more particular subject of the present invention is the products de formula (I) as defined above, in which R1 represents a phenyl or biphenyl radical, optionally substituted by a halogen atom, or by a hydroxyl radical optionally in the form of the trifluoromethyl-sulphonyloxy radical,
n1 represents the integer 1,
n2 represents the integer 0,
R2 represents a hydrogen atom or a methyl radical substituted by a phenyl radical, itself optionally substituted by a thienyl or phenyl radical itself optionally substituted by a cyano radical,
A represents the free, salified, esterified ou amidified carboxy radical or an alkyl radical, containing at most 10 carbon atoms substituted by a phenoxy radical,
said products of formula (I) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic bases of said products of formula (I).
In particular, R1 can represent a phenyl or biphenyl radical, optionally substituted by a bromine atom.
A quite particular subject of the present invention is the products de formula (I) as defined above, the names of which follow:
[S-(R*,S*)]N-[1-(mercaptomethyl)-2-phenylethyl]-alpha-[[(phenylmethoxy) carbonyl]amino]-1H-indole-3-propanamide,
2xe2x80x2-cyano-alpha-[[[1-(mercaptomethyl)-2-phenylethyl]amino]carbonyl](1,1xe2x80x2-biphenyl)-4-propanoic acid,
(R)N-(1-mercaptomethyl)-2-phenylethyl)-11-phenoxy-undecanamide,
said products of formula (I) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with mineral and organic bases of said products of formula (I).
A subject of the present invention is also the preparation process for the products of formula (I), such as defined above, characterized in that a product of formula (II) 
in which n1 has the meaning indicated above and Rxe2x80x21 has the meaning indicated above for R1 in which the optional reactive functions are optionally protected, is subjected either to the action of a compound of formula (III): 
in which Rxe2x80x22 has the meaning indicated above for R2 in which the optional reactive functions are optionally protected, and R represents an alkyl or arylalkyl radical, in order to obtain the product of formula (IV): 
in which n1, Rxe2x80x21, Rxe2x80x22 and R have the meanings indicated above, or to the action of an acid halide of formula (V): 
in which n2 has the meaning indicated above, Hal represents a halogen atom, Rxe2x80x22 has the meaning indicated above and Axe2x80x2 has the meaning indicated above for A in which the optional reactive functions are optionally protected, such as in particular Axe2x80x2 does not represent a free carboxy radical, in order to obtain a product of formula (VI): 
in which n1, n2, Rxe2x80x21, Rxe2x80x22 and Axe2x80x2 have the meanings indicated above,
which products of formula (IV) and (VI), in order to obtain products of formula (I) or to convert the products of formula (I) into other products of formula (I), can be treated, if desired and if necessary, to one or more of the following reactions, in any order:
a saponification reaction of the ester function into an acid function,
a conversion reaction of the cyano function or amide function into an acid or tetrazolyl function,
a conversion reaction of the alkoxy function into the hydroxyl function,
an esterification, salification or amidification reaction of the acid function,
a reaction which releases the thiol function from the 
an elimination reaction of the protective groups which can be carried by the protected reactive functions,
a salification reaction by a mineral or organic acid or base in order to obtain the corresponding salt, said products of formula (I) thus obtained being in all possible racemic, enantiomeric and diastereoisomeric isomer forms.
Under the preferred conditions for implementing the invention, the process described above can be carried out in the following fashion:
the reaction of the product of formula (I) as defined above with the product of formula (III) as defined above is preferably carried out with a coupling agent such as for example EDC in methylene chloride or also BOP methyl cyanide in the presence of triethylamine, or also DDC,
the reaction of the product of formula (II) as defined above with the product of formula (V) as defined above is preferably carried out, in methylene chloride in the presence of pyridine. In the compound of formula (V), the halogen atom is preferably a chlorine atom.
According to the values of Rxe2x80x21, Rxe2x80x22 and Axe2x80x2, the products of formulae (IV) and (VI) constitute or do not constitute products of formula (I) and can produce products of formula (I), or be converted into other products of formula (I) by being subjected to one or more of the reactions indicated above which can be carried out, for example, as indicated hereafter.
The various reactive functions which can be carried by certain compounds of the reactions defined above can, if necessary, be protected: it is for example the hydroxyl or free carboxy radicals which can be protected by the appropriate protective groups.
The following non-exhaustive list, of examples of the protection of reactive functions can be mentioned:
the amine groups can be protected in the form of other carbamates, such as those known in the chemistry of peptides,
the hydroxyl groups can be protected for example by alkyl radicals such as tert-butyl, trimethylsilyl, tert-butyldimethylsilyl, methoxymethyl, tetrahydropyrannyl, benzyl or acetyl.
The products described above can, if desired, be the object, on the optional carboxy functions, of esterification, salification or amidification reactions, which can be carried out according the usual methods known to a person skilled in the art.
The acid functions of the products described above can be, if desired, amidified by a primary or secondary amine for example in methylene chloride in the presence of, for example, 1-ethyl-3-(dimethylaminopropyl) carbodiimide hydrochloride at ambient temperature.
The acid functions acid can be protected for example in the form of esters formed with easily cleavable esters such as benzylic or ter butylic esters or esters known in the chemistry of the peptides.
The optional saponification reactions of the ester function into an acid function of the products described above can, if desired, be carried out under the usual conditions known to a person skilled in the art in particular by acid or alkaline hydrolysis for example with soda or potash in alcoholic medium such as, for example, in methanol or also with hydrochloric or sulphuric acid.
The optional cyano functions of the products described above can, if desired, be converted into an acid function under the usual conditions known to a person skilled in the art for example by a double hydrolysis carried out in acid medium such as for example in a sulphuric acid, glacial acetic acid and water mixture, these three compounds preferably being in equal proportions, or also in a soda, ethanol and water mixture under reflux.
The optional cyano functions of the products described above can, if desired, be converted into the tetrazolyl function under the usual conditions known to a person skilled in the art such as for example by the cycloaddition of a metal azide such as for example sodium azide or trialkyltin azide on the nitrile function as indicated in the method described in the article referenced as follows: J. Organometallic Chemistry., 33, 337 (1971) KOZIMA S.and al.
The acid functions can be converted into tetrazole as indicated in the publication Bio. Med. Chem. Leh. 1995, 145.
The optional alkoxy functions such as in particular methoxy of the products described above can, if desired, be converted into the hydroxyl function under the usual conditions known to a person skilled in the art for example with boron tribromide in a solvent such as for example methylene chloride, with pyridine hydrobromide or hydrochloride or also with hydrobromic or hydrochloric acid in water or trifluoroacetic acid under reflux.
The optional hydroxyl functions of the products described above can, if desired, be converted into an acid function by oxidation under the usual conditions known to a person skilled in the art in the conditions such as for example by the action of Jones reagent to access the acids.
The elimination of the protective groups such as for example those indicated above can be carried out under the usual conditions known to a person skilled in the art in particular by an acid hydrolysis carried out with an acid such as hydrochloric, benzene sulphonic or paratoluene sulphonic, formic or trifluoroacetic acid or also by catalytic hydrogenation.
The phthalimido group can be eliminated with hydrazine.
A list of the different protective groups that can be used will be found for example in the Patent BF 2 499 995.
The products described above can, if desired, be the object of salification reactions for example with a mineral or organic acid or with a mineral or organic base according to the usual methods known to a person skilled in the art.
The optional optically active forms of the products described above can be prepared by resolution of the racemics according to the usual methods known to a person skilled in the art.
Illustrations of such reactions defined above are given in the preparation of the examples described hereafter.
The structures and properties of endothelin and of its precursor Big Endothelin are described in the literature such as for example in the document WO 93/11154.
The products of formula (I) of the present invention have been found to have an inhibitory activity on the enothelin-converting enzyme which allows the properly so-called endothelin to be obtained from Big Endothelin, which is thus an extremely powerful vasoconstrictor agent.
The products of formula (I) of the present invention can therefore be used in the treatment of illnesses resulting from abnormally high quantities of endothelin.
The compounds of formula (I) as defined above as well as their addition salts as defined above have useful pharmacological properties.
The products of formula (I) as defined above, endowed with inhibitory properties of the endothelin-converting enzyme, can thus in particular reduce the quantities and therefore the effects of endothelin, in particular the vasoconstrictor and hypertensor effects induced by endothelin. In particular an antiischemic effect is noted.
The products of formula (I) therefore also have the effect of reducing the stimulating effects of endothelin at the level of all cell types, in particular the smooth muscle cells, the fibroblasts, the neuronal cells and the bone cells.
These properties justify their use in therapeutics and a particular subject of the invention is as medicaments, the products of formula (I),
said products of formula (I) being in all possible racemic, enantiomeric and diastereoisomeric isomer forms, as well as the addition salts with pharmaceutically acceptable mineral and organic acids or with pharmaceutically acceptable mineral and organic bases of said products of formula (I).
More particularly a subject of the invention is also, as medicaments, the preferred products as defined by formula (I) above in which;
R1 represents a phenyl or biphenyl radical, optionally substituted by halogen atom,
n1 represents the integer 1,
n2 represents the integer 0,
R2 represents a hydrogen atom or a methyl radical substituted by a phenyl radical, itself optionally substituted by a thienyl or phenyl radical itself optionally substituted by a cyano radical,
A represents the free, salified, esterified or amidified carboxy radical or an alkyl radical, containing at most 10 carbon atoms substituted by a phenoxy radical,
said products of formula (I) being in all possible racemic, or optically active isomer forms, as well as the addition salts with pharmaceutically acceptable mineral and organic acids or with pharmaceutically acceptable mineral and organic bases of said products of formula (I).
A quite particular subject of the invention is, as medicaments, the products described hereafter in the examples and in particular the products of formula (I) as defined above, the names of which follow:
[S-(R*,S*)]N-[1-(mercaptomethyl)-2-phenylethyl]-alpha-[[(phenylmethoxy) carbonyl]amino]-1H-indole-3-propanamide,
2xe2x80x2-cyano-alpha-[[[1-(mercaptomethyl)-2-phenylethyl]amino]carbonyl](1,1xe2x80x2-biphenyl)-4-propanoic acid,
(R)N-(1-mercaptomethyl)-2-phenylethyl)-11-phenoxy-undecanamide,
as well as the addition salts with pharmaceutically acceptable mineral and organic bases of said products of formula (I).
The medicaments, which are a subject of the invention, therefore find their use in the treatment, by use of an inhibitory agent of the endothelin-converting enzyme, for illnesses such as, for example, vascular spasms, vasospasm as a result of a cerebral haemorrhage, coronary spasms, peripheral vascular spasms as well as renal insufficiencies. These medicaments can also be used in the treatment of myocardial infarction, of congestive cardiac insufficiency, in the prevention of post-angioplasty recurrence of stenosis, of cardiac and vascular fibrosis, in the treatment of atherosclerosis, of certain forms of hypertension such as in particular pulmonary hypertension, as well as in the treatment of asthma.
The medicaments, which are a subject of the invention, can also find a use in the treatment of osteoporosis, prostatic hypertrophia and as neuronal protectors.
The invention extends to the pharmaceutical compositions containing as active ingredient at least one of the medicaments as defined above.
These pharmaceutical compositions can be administered by buccal, rectal route, by parenteral route or by local route as a topical application on the skin and mucous membranes or by injection by intravenous or intramuscular route.
These compositions can be solid or liquid and be presented in all the pharmaceutical forms commonly used in human medicine, such as for example, plain or sugar-coated tablets, capsules, granules, suppositories, injectable preparations, ointments, creams, gels and aerosol preparations; they are prepared according to the usual methods. The active ingredient can be incorporated with excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.
The usual dose, variable according the product used, the patient treated and the illness in question, can be, for example, from 1 to 300 mg per day in an adult, by oral route or from 1 to 100 mg per day by intravenous route.
Certain starting products of formula (II), (III) and (V) are known, may be commercially available or prepared according to the usual methods known to a person skilled in the art or also for example as indicated in the European Patent EP 0465369.
In particular certain products of formula (II) can also be prepared from other products of formula (II) for example by subjecting them to one or more of the reactions described above, carried out under the conditions also described above.
Preparations for the compounds of formula (II) are indicated in the examples described hereafter.
It should be noted that the compound of formula (II) can be in racemic or optically pure form and that, consequently, the product of formula (IV) obtained can also be in racemic or optically pure form.
The compound of formula (II) in which ni represents the integer 1 and Rxe2x80x21 represents the phenyl radical can be prepared as indicated in Preparation 1E of EP 0465369, either starting with the amino acid L-phenylalamine in order to produce the product of formula (II) of form S, or starting with the amino acid D-phenylalamine in order to produce the product of formula (II) of form R, or starting with a mixture of amino acids, L- and D-phenylalamine in order to produce the product of formula (II) of racemic form: these compounds of formula (II) thus obtained produce respectively, after reaction with the compound of formula (III), a product of formula (IV) which will be respectively in {circle around (1)} in S form (Example 1), in R form (Example 2) or in racemic form (Example 5).
Other compounds of formula (II), can be obtained in the same fashion starting from other amino acids.
In particular, the products of formula (II) in which Rxe2x80x21 represents the biphenyl radical can be obtained starting from tyrosine.
Such a reaction is indicated in the preparation of Example 7, described hereafter.
Other compounds of formula (II), in which n1 represents the integer 0 can be prepared starting from the corresponding acid in order to produce by a Curtius reaction described in the literature, the sought amine.
The compounds of formula (III) represent amino acids which can be substituted on the nitrogen: such compounds of formula (III) may be commercially available or be prepared according to the usual methods known to a person skilled in the art.
The compounds of formula (V) are preferably acid chlorides prepared from the corresponding acid itself commercially available or prepared according to the usual methods known to a person skilled in the art, such as by condensation of an alkyl halide on a malonate.
Finally, a subject of the present invention is, as new industrial products, the compounds of formulae (IV) and (VI) as defined above.
Particularly a subject of the present invention is the use of the products of formula (I) as defined above, for the preparation of an inhibitory agent of the endothelin-converting enzyme.
Therefore a particular subject of the present invention is the use of the products of formula (I) as defined above, for the preparation pharmaceutical compositions intended for the treatment, by inhibition of the endothelin-converting enzyme, for illnesses such as, in particular, hypertension induced by endothelin, vascular spasms, the effects of a cerebral haemorrhage, renal insufficiencies, myocardial infarction , cardiac insufficiency as well as the prevention of post-angioplasty recurrence of stenosis and cardiac and vascular fibrosis.